Generally employed for crystallizing 3-cephem derivatives are crystallization methods using a combination of a good solvent which is superior in the power of dissolving the substrate and a poor solvent which is inferior in the power of dissolving the substrate.
However, these conventional crystallization methods have the following defect. The poor solvent partly becomes highly concentrated in the crystallization system when the poor solvent is dispersed in the good solvent, so that an amorphous powder is produced in most cases without formation of crystalline nucleus because of abrupt deposition occurring in the part. In addition, the obtained 3-cephem derivative is very unlikely to have enhanced purity because it generally contains impurities.
The amorphous powder, compared with crystalline powder, tends to raise troubles such as leakage and clogging in filter cloth and thus a significantly prolonged time for filtration, and reduction of purity due to insufficient washing. Conventional methods for crystallizing 3-cephem derivatives generally involve an increased loss of filtrate under mild conditions approximately at room temperature and fail to give the contemplated product in a sufficient yield because of marked temperature dependency of substrate solubility in the solvent used.
Since 3-cephem derivatives have a high affinity for organic solvents, conventional crystallization methods using a large amount of organic solvent increase the adsorption quantity of organic solvent, making it very difficult in most cases to remove the remaining solvent by drying. Further, an amorphous powder of 3-cephem derivative is generally low in heat stability and thus entails difficulty in drying at high temperatures, necessitating drying under a high vacuum. For this reason, conventional crystallization methods give only amorphous powders. In the foregoing situation, there is an ardent demand for a novel method for crsytallization of 3-cephem derivatives.
On the other hand, attempts have been reportedly made to develop a new crystallization technology using carbon dioxide in a supercritical state as a poor solvent [Chemical Engineering Symposium Series: Vol.49, p.p.200 to 205 (1995), Idemitsu Giho: Vol.35, No.5, p.p.600 to 606 (1992), etc.]. These reports describe crystallization techniques for converting stable substances which are inherently crystalline, suggesting nothing on the possibility of crystallizing unstable compounds such as those which can be made into only an amorphous powder by conventional methods.
An object of the present invention is to provide a novel process for preparing crystals which process can produce a high-purity 3-cephem derivative in crystalline form from an amorphous powder or oil of a 3-cephem derivative whose stability is very important.